: For the newborn, the neonatal period is a physiologic transition from maternal-dependence to self-reliance. At this time the immune system faces the challenge of relocating from the sterile intra-utero milieu to a world of allergens and microbes where protection is critical. Yet, injection of antigen during the neonatal stage often leads to tolerance, and only a few vaccines work in human neonates. Initially, deletion and/or inactivation of T cells were considered the leading mechanisms for neonatal tolerance. However, recent investigations have revealed that the neonatal immune system can be regulated and guided to develop T cell immunity. For instance, if a peptide is injected into neonates in adjuvant immunity develops. The essence of this observation is that approaches can be devised that could force the neonatal immune system to be responsive, providing an opportunity to analyze and comprehend its mode of action. The objectives in this application seek to enlighten our comprehension of this understudied area of neonatal immunity. Both cellular and molecular aspects of neonatal immunity will be examined. The application under consideration employs a novel approach to trigger neonatal immunity, and the preliminary studies outline a unique mechanism the neonatal immune system utilizes to control T cells. This approach uses genetically engineered immunoglobulins (Igs) incorporating antigenic peptides as vehicles for delivery of such peptides into antigen presenting cells and stimulation of T cells. The rational for this delivery system is that it increases peptide presentation by several orders of magnitude relative to free peptide and involves regulatory functions influential for costimulation and T cell differentiation. Indeed, when an Ig-peptide chimera was given to mice in saline on the day of birth it induced a neonatal immunity that protected animals against the development of the autoimmune disease known as experimental allergic encephalomyelitis. Herein, we propose to investigate the mechanism underlying such protective neonatal immunity and hopefully enlighten our comprehension of neonatal immunity. Understanding how the neonatal immune system functions is a prerequisite for the development of neonatal vaccines.